1. Area of the Art
The present invention deals with disinfection in the medical area and in particular agents that greatly potentiate the activity of known antimicrobial and disinfection agents.
2. Description of the Prior Art
It has long been known that various chemical agents can be used to kill or otherwise limit the growth of infectious agents such as bacteria and viruses. Many of the initial disinfecting materials were active, even caustic, chemicals such as the “carbolic acid” (phenol) used by Lister in the early days of the germ theory of disease. In the last century anti-infective agents of biological origin such as penicillin, were discovered and widely exploited. Antibiotic drugs used to treat infectious diseases have proliferated and were used liberally in developed countries following the Second World War. These drugs are widely used not only to treat disease but to obtain enhanced growth of farm animals living under often substandard “factory farm” conditions. As a result of this sort of excessive use and misuse by patients, many new, antibiotic resistant organisms have evolved. Drug companies and researchers are actively seeking new compounds to fight these resistant disease organisms. Most of their research however is targeted at finding single chemical compounds or combinations of chemical compounds that act on these organisms.
Combination therapies have been around for many years as demonstrated in the book “Combination Antibiotic Therapy in the Compromised Host”, edited by J. Klastersky and MJ Staquet, New York, Raven Press, 1982. Other more recent work on combination therapies is the work done with fluoroquinolones (Meyer, RD, J. Antimicrob. Chemother., 1991, 28, 623). The general idea of combination therapy is to develop a synergistic drug combination or to somehow enhance the activity of a known antibiotic or even some other disinfectant or anti-infective agent. In many instances combination therapies are sought as ways to overcome drug resistant disease organisms. For example, penicillin, the first widely used antibiotic, has now lost much of its usefulness due to resistant organisms. One form of penicillin resistance involves the production of penicillin destroying enzymes (penicillinase) by disease organisms. Therefore, one type of combination therapy is to combine compounds that inhibit penicillinase with the penicillin. This approach can largely restore the resistant organism's sensitivity to penicillin.
Antibiotics are natural biological compounds often of bacterial or fungal origin. Many of our drugs are of plant origin. Therefore, it is hardly surprising that much research is now being conducted in the area of the antimicrobial qualities of herbs, fruit extracts and other materials of plant origin. For the most part, companies and researchers are studying the efficacy of extracts of plant materials, alone or the efficacy of specific purified molecules of the plant material extracts. A series of patents by Walker et al. (U.S. Pat. Nos. 5,474,774, 5,525,341, 5,646,178, and 5,650,432) describe the isolation and purification of specific compounds from cranberry for use as antimicrobials. In particular it was demonstrated that these agents interfere with the adhesion of bacteria to the endothelial cells of the urinary tract. The present inventor has purified antimicrobial colored compounds from cranberry and other plant materials. These compounds actually have bacteriostatic as well as bactericidal and virucidal activities as described in U.S. Pat. No. 6,093,401.
The present inventor has long had an interest in disinfecting blood and blood products. Out of this interest the just mentioned interest in antimicrobial plant products developed. From his many years of experience with blood fractionation and production of blood products the present inventor was extremely familiar with the use of various chemicals as anticoagulants in blood and blood products. Common anticoagulants are EDTA, heparin, oxalic acid, citric acid and their salts. Of these all but heparin function primarily by reducing the level of calcium ions. One of the inventor's experiments aimed at disinfecting blood plasma inadvertently removed the citric acid (actually sodium citrate) used as an anticoagulant with the resulting precipitation (coagulation) of the plasma. Attempts were made to overcome this problem through the addition of extra citric acid. This resulted in the present discovery of the unexpected properties of citric acid, which forms the substance of the present invention.
It should be appreciated that there is a pressing need for the disinfection of blood and blood products used for transfusion and other medical therapies. In the first place collected blood is virtually always contaminated with bacteria commonly present on the skin of the blood donor. The needle used for blood donation picks up these organisms and contributes them to the donated blood. These bacteria especially cause problems with platelet concentrates whose useful life is currently limited to five days because of bacterial growth whereas the biologically useful life of the concentrates is at least several additional days. With the current shortages of donated blood this rapid outdating of platelet concentrates is especially troublesome.
Another reason for disinfection is the one that occurs to most people concerned with blood safety-namely blood borne disease. When the blood donor is infected with viral or other disease agents, the infection may be spread through blood transfusion or receipt of blood products made from infected blood. Currently a detergent-based process, originated by the present inventor, is used to inactivate many viruses present in blood plasma. This results in safer plasma and blood products made therefrom. However, detergents cannot be used on whole blood because they damage or destroy blood cells. Thus, there is a great need for methods to disinfect whole blood and cellular fractions thereof. Further, the current detergent process does not inactivate all dangerous blood borne viruses. Therefore, there is also a pressing need for improved disinfection of plasma.
The present inventor has discovered that increasing the concentration of citrate to levels higher than those usual for anticoagulation results in significant decreases in bacteria and bacterial growth in blood and blood fractions. Further, citrate shows an unexpected synergistic effect when combined with a wide variety of antibiotics, antimicrobials and disinfecting agents including iodine and natural plant products such as those from grape of cranberry. Citrate has been used in dental rinses and is widely used as an anticoagulant and a buffering agent in foods, pharmaceuticals and cleaning materials. However, the antimicrobial synergistic effects of citrate have hitherto not been appreciated.